Orthoalkylated anilines and phenols are important building blocks in the preparation of plant protection agents, pharmaceuticals and other fine chemicals. Classical Friedel-Crafts alkylation of anilines and phenols typically leads to para as well as ortho alkylation, and furthermore often results in polyalkylation. While Friedel-Crafts acylation of anilines and phenols typically gives only monosubstitution, substitution still can occur at the para as well as ortho positions, and reaction conditions needed for reductive removal of the acyl carbonyl moiety may be incompatible with other functionality on the molecule.
In the 1970s, Paul Gassman led the development of an alternative synthetic method affording regioselective orthoalkylation (for lead references see P. G. Gassman and G. Gruetzmacher, J. Am. Chem. Soc. 1973, 95, 588–589; P. G. Gassman and G. Gruetzmacher, Org. Syn., Coll. Vol. VI, 581–583; P. G. Gassman and H. R. Drewes, J. Am. Chem. Soc. 1978, 100, 7600–7610; P. G. Gassman and D. R. Amick, J. Am. Chem. Soc. 1978, 100, 7611–7619). The Gassman method involves generating an intermediate species believed to have the Formula i from the aniline or phenol and an alkyl thioether such as dimethyl sulfide and oxidizing agents such as tert-butyl hypochlorite or chlorine.
wherein A is NH or O, and (R)p denotes optional substituents.
Treatment with base such as triethylamine or sodium methoxide effects rearrangement to give an ortho alkylthioalkyl compound illustrated by Formula ii.
wherein A is NH or O, and (R)p denotes optional substituents.
Lastly, desulfurization treatment with Raney nickel cleaves the alkylthioalkyl group to an alkyl group as illustrated by Formula iii.
wherein A is NH or O, and (R)p denotes optional substituents.
While this method offers an attractive alternative to Friedel-Crafts methods of aromatic alkylation, its conditions are not ideal for preparation on an industrial scale. Particularly disadvantageous is its use of Raney nickel to cleave the alkylthioalkyl group to alkyl. Raney nickel is used as a reagent instead of a true catalyst and thus is expensive. Moreover, it is pyrophoric and must be kept covered with water. Although slurrying the spent material in water and flushing down the drain is suggested by P. G. Gassman, G. Gruetzmacher, Org. Syn., Coll. Vol. VI, 581–583, this article recognizes such disposal to be environmentally unsound. A more satisfactory alternative to Raney nickel is needed for industrial manufacture using this method.
Another disadvantage of this method is that the procedures used to prepare species illustrated by Formula i often rely upon cold temperatures, as low as −50° C. As refrigeration is expensive, the need to maintain such low temperatures is undesirable in industrial manufacture of chemicals.
A. D. Dawson and D. Swern (J. Org. Chem. 1977, 42, 592–597) report preparation and isolation of the species illustrated by Formula i by treatment of anilines with dimethyl sulfide activated by N-chlorosuccinimide or N-chlorobenzotriazole, again at low temperatures. This reference does not disclose rearrangement to compounds illustrated by Formula ii. U.S. Pat. No. 4,496,765 discloses preparation of an ylid of Formula iv by washing with aqueous sodium hydroxide solution a dichloromethane solution of the corresponding compound of Formula i, which is formed from 2-(trifluoromethyl)-aniline, dimethyl sulfide and N-chlorosuccinimide.
wherein (R)p denotes optional substituents.
U.S. Pat. No. 4,496,765 also discloses preparation of a compound of Formula ii by heating the ylid of Formula iv, optionally in the presence of catalytic succinimide.
P. Claus and W. Vycudilik (Tetrahedron Lett. 1968, 3607–3610; Monatsch. Chem. 1970, 101, 396–404) report that anilines can be transformed into readily isolable ylids illustrated by Formula iv by treatment with dimethyl sulfoxide, phosphorus pentoxide and triethylamine in chloroform at temperatures near room temperature. In this reaction, the triethylamine base may be presumed to deprotonate an intermediate species illustrated by Formula i. The intermediate ylids illustrated by Formula iv are then reported to rearrange to ortho alkylthioalkyl compounds illustrated by Formula ii in the presence of bases such as triethylamine or in protic solvents such as alcohols and water even without the addition of base (see also P. Claus and W. Rieder, Monatsh. Chem. 1972, 103, 1163–1177). As this method avoids need for low temperatures, it is industrially more attractive, but the cost of phosphorus pentoxide and disposing of phosphorus wastes would be of concern industrially. These references do not address the desulfurization conversion of Formula ii to Formula iii.
Because of potentially lower cost and easier treatment of waste, sulfur trioxide is more industrially attractive than phosphorus pentoxide. U.S. Pat. No. 3,527,810 discloses a process for preparing the sulfur trioxide complex with dimethyl sulfoxide, and T. E. Varkey, G. F. Whitfield and D. Swem (J. Org. Chem. 1974, 39, 3365–3372) report the use of sulfur trioxide to activate dimethyl sulfoxide in reaction with aromatic amines to form ylids illustrated by Formula iv after treatment with base. For the reaction of the sulfur trioxide complex of dimethyl sulfoxide with p-toluenesulfonamide, this reference reports cosolvents such as chloroform giving lower yields. For the reaction of the sulfur trioxide complex of dimethyl sulfoxide with aromatic amines, this reference avoids a cosolvent and teaches a ratio of DMSO:SO3: aromatic amine of 4–6:1:0.6–0.9, and recommends this over a DMSO:SO3 ratio of 2–3:1. This reference also describes use of acetic anhydride, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, cyclohexylcarbodiimide and phosphorus pentoxide as activating agents for dimethyl sulfoxide. The reference does not report rearrangement of the ylids from aromatic amines.
None of the above references disclose useful alternatives to Raney nickel for the desulfurization conversion of Formula ii to Formula iii required by this method. U.S. Pat. Nos. 4,404,069 and 4,806,687 disclose such alternatives.
U.S. Pat. No. 4,404,069 uses electrolytic desulfurization to reduce 2-(methylthio-methyl)-6-(trifluoromethyl)aniline or its corresponding sulfoxide or sulfone to 2-methyl-6-(trifluoromethyl)aniline. This method requires use of large amounts of quaternary ammonium salt electrolytes in addition to polar solvents, in which organic substances may not be highly soluble. U.S. Pat. No. 4,404,069 reports that sulfoxides and sulfones are more easily reduced than sulfides. Oxidation of sulfides to sulfoxides or sulfones requires an additional step. An undesirable potential side reaction is reduction of halogen substituents. To avoid reduction of trifluoromethyl to difluoromethyl, U.S. Pat. No. 4,404,069 recommends stopping the reaction before conversions exceed 85–90% or continuously extracting the product from the polar reaction mixture, which may also be needed to prevent phase separation of the reactant and product from the polar reaction medium.
U.S. Pat. No. 4,806,687 uses hydrodesulfurization with a presulfided cobalt-molybdenum catalyst to reduce 2-(methylthiomethyl)-6-(trifluoromethyl)aniline to 2-methyl-6-(trifluoromethyl)aniline. The preferred temperature for this reaction is 150 to 250° C. Moreover, a hydrogen pressure of more than 3400 kPa is preferred to obtain practical reaction rates.
In view of the process requirements and limitations of these methods, further improvements are still needed to effect the desulfurization conversion of Formula ii to Formula iii. Such an improvement has now been discovered.